Brain and Behavioral Indicators of Risk for Parkinsonism among Adolescents with Early Pesticide Exposure

多项研究表明，接触有机磷(OP)杀虫剂与 成人帕金森氏病(PD)，但几乎没有研究探索致病过程的迹象 早在运动症状出现之前就开始了。显然有必要进行前瞻性研究，包括 暴露的生物标记物和基于大脑的措施，以证实因果关系和 随着时间的推移，帕金森症的发展。我们可以访问一个具有良好特征的社区样本-An 城市少数民族出生队列已跟踪18年，产前血液生物标记物暴露于 一种常见的OP杀虫剂毒死蜱(CPF)，以及对神经发育的定期评估，包括 12-14岁和18岁的多模式脑部扫描。在这个队列中，我们已经证明了产前CPF暴露是 与2-3年的运动延迟有关，以及持续的大脑、行为和微妙的运动影响- 12岁。我们现在有一个独特的机会来研究临床前/非运动性疾病的出现 该队列中18-20岁的帕金森病风险指标。我们建议检验这一新的假设，即产前 CPF暴露有长期的运动后果，包括神经体征和基于大脑的生物标记物 帕金森病风险可在发病过程的早期测量，在临床确诊之前 症状或诊断。我们的目标是：(1)进行单一波的神经和脑成像评估 (使用成人人口中PD风险的已知指标)在18-20岁的队列(n=200)的子组中。 我们假设，那些产前CPF水平较高的人与那些较低水平的人相比将显示出 明显更多的早期帕金森病风险迹象，如(A)临床前锥体外系综合征的较高患病率 运动功能障碍(肌张力障碍、运动迟缓、手臂震颤)；(B)非运动症状(REM)发生率较高 睡眠行为障碍、自主神经功能障碍、嗅觉障碍)；和(C)前驱运动标志物增加 (2)步态多变、行走方式不一致、手臂摆动不对称、轴向旋转平稳度较低)； 对神经黑素进行结构磁共振成像以确定黑质受累(帕金森病的生物标志物)。 同样的主题。我们推测，与出生前CPF水平较低的人相比，产前CPF水平较高的人 水平将显示显著更多的黑质受累，标志是更大程度的下降 神经黑色素含量；(3)采用创新的统计程序，使用大量的功能和 基于之前在12-14和18岁收集的多模式成像数据的大脑结构特征， 以确定与暴露相关的跨模式神经缺陷模式(一个潜在的生物标记物 帕金森病)可以在我们的年轻队列中检测到。我们假设产前CPF水平较高的受试者为 与那些水平较低的人相比，这些人将显示出不同的大脑异常模式 时间到了。这项研究有可能改变研究范式，不再关注神经退行性过程 在帕金森病中纳入神经发育观点，对未来的干预具有潜在的影响。

Multiple studies have demonstrated an association between organophosphate (OP) insecticide exposure and Parkinson's Disease (PD) in adults, but virtually no studies have explored signs of the pathogenic process that begins long before the appearance of motor symptoms. There is a clear need for prospective studies, including biomarkers of exposure and brain-based measures, to substantiate a cause-effect relationship and the development of parkinsonism over time. We have access to a well-characterized community sample—an urban minority birth cohort that has been followed for 18 years, with a prenatal blood biomarker of exposure to a common OP pesticide, chlorpyrifos (CPF), and regular assessments of neurodevelopment, including multimodal brain scans at 12-14 and 18 years. In this cohort, we have shown that prenatal CPF exposure is associated with motor delay at 2-3 years, and persistent brain, behavioral and subtle motor effects through 11- 12 years of age. We now have a unique opportunity to study the emergence of pre-clinical/non-motor indicators of PD risk at 18-20 years of age in this cohort. We propose to test the novel hypothesis that prenatal CPF exposure has long-term motor consequences, including neurological signs and brain-based biomarkers of PD risk that are measureable early in the pathogenic process, prior to the identification of clinically confirmed symptoms or diagnosis. We aim to: (1) conduct a single wave of neurological and brain imaging assessment (using known indicators of PD risk in adult populations) in a subset of the cohort (n=200) at 18-20 years of age. We hypothesize that those with higher prenatal CPF levels as compared to those with lower levels will show significantly more signs of early PD risk, as indicated by (a) higher prevalence of pre-clinical extrapyramidal motor dysfunction (dystonia, bradykinesia, arm tremor); (b) higher prevalence of non-motor symptoms (REM sleep behavior disorder, autonomic dysfunction, olfactory deficits); and (c) increased prodromal motor markers (gait variability, inconsistent walking pattern, arm swing asymmetry and lower axial rotation smoothness); (2) conduct structural MRI for neuromelanin to identify substantia nigra involvement (a biomarker of PD) in these same subjects. We hypothesize that those with higher prenatal CPF levels as compared to those with lower levels will show significantly greater substantia nigra involvement marked by a greater decrease in neuromelanin content; (3) employ an innovative statistical procedure using a vast number of functional and structural brain characteristics, based on multi-modal imaging data previously collected at 12-14 and 18 years, to determine whether an exposure-related pattern of neural deficits across modalities (a potential biomarker for PD) can be detected in our young cohort. We hypothesize that subjects with higher prenatal CPF levels as compared to those with lower levels will show a distinctive pattern of brain anomalies across modalities and time. This study has the potential to shift the research paradigm from a focus on neurodegenerative processes in PD to incorporate a neurodevelopmental perspective, with potential implications for future interventions.